Submissions for variant NM_000179.3(MSH6):c.1111G>C (p.Glu371Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002292237	SCV002584670	uncertain significance	Lynch syndrome 5	2022-09-27	criteria provided, single submitter	clinical testing	The MSH6 c.1111G>C (p.Glu371Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV002434624	SCV002748089	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-18	criteria provided, single submitter	clinical testing	The p.E371Q variant (also known as c.1111G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 1111. The glutamic acid at codon 371 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV002434624	SCV004357572	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 371 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.